There are five known herpes-type viruses which affect human beings: herpes zoster (chicken pox), herpes simplex virus I & II (cold sores and genital herpes), cytomegalovirus (cytomegalic inclusion disease), and Epstein-Barr virus (mononucleosis). The herpes viruses are medium-sized viruses containing double-stranded DNA. The nucleocapsid is about 100 nm in diameter and is surrounded by a lipid containing envelope. The virion is 150-200 nm in diameter, and permits latent infections which last for the life span of the host even when antibodies are present.
A very different group of virus particles is the RNA virus group. Of particular interest within this group are the retroviruses which include most tumor virions, including human T-cell leukemia virus (HTLV III), now designated human immunodeficiency virus (HIV). HIV or its close relatives are believed to be the cause of Acquired Immune Deficiency Syndrome (AIDS).
General antiviral agents are numerous. Several nucleoside analogs, such as iododeoxyuridine and 5-E-bromovinyldeoxyuridine, are believed to act only after conversion by viral thymidine kinase (but not by host TK) to the nucleotide form, which is then converted to the triphosphate and incorporated into the viral DNA, thus inhibiting its replication. These analogs are ineffective in certain herpes strains which are TK.sup.-, and even TK.sup.+ strains resistant to certain specific members of this class of agents have been reported (Field, H., et al, J Infect Disease (1981) 143:281; Hirano, A., et al, Acta Virol (1979) 23:226). It would not be expected that agents which work by this mechanism would be effective against RNA viruses.
The antiviral agents of the present invention are acyclic nucleotide analogs which are phosphonates rather than phosphates. A large number of phosphonate analogs of nucleotides are described by Engel, R., Chem Reviews (1977) 11: (3) 349-367. Phosphonate compounds which are direct cyclic nucleotide analogs are also disclosed in U.S. Pat. No. 3,560,478; German Patent Application No. DE 3,045,375VA1, published July 1, 1982; U.S. Pat. No. 3,446,793; British Patent No. 1,243,213; German Patent Application No. 2,009,834 published Sept. 17, 1970 and in Holman, J., et al, Liebigs Annalen Chem (1984) 98-107; Hampton, A., et al, Biochemistry (1973) 12:1730-1736; Jones, G. H., et al, J Am Chem Soc (1968) 90:5337-5338; Montgomery, J. A., et al, J Med Chem (1979) 22:109-111 and British Patent No. 1,243,214. In general, in the foregoing disclosures, the utility of the phosphonates is believed to reside in their structure being analogous to that of the nucleotides combined with enhanced stability due to the phosphonate moiety. In general, it is suggested that they are useful for whatever pharmacological purposes the corresponding nucleotides would serve.
For example, Montgomery, J., et al, J Med Chem (supra), suggest that the phosphonate analogs may be useful as cytotoxic agents analogous to the commonly used chemotherapeutic drug 5-fluorouracil by virtue of a similar ability to inhibit the essential enzyme thymidilate synthetase, essential for DNA synthesis. This enzyme is inhibited actually by the anabolic product of 5-fluorouracil, the corresponding monophosphate.
All of the foregoing referenced compounds retain the furanose cyclic structure of the ribose or deoxyribose. Nucleoside analogs in which the cyclic furanose structure is replaced by an open chain are well known antiviral agents. French Patent Application Publication No. 2,381,781 discloses these acyclic purine nucleosides and nucleotides; similar compounds are disclosed in EPO Application Publication Nos. 0049072 and 0074306. Antiviral activity of some of these compounds with regard to herpes simplex virus is confirmed, for example, by Kelley, J. L., et al, J Med Chem (1981) 34:1528-1531.
St. Clair, M. H., et al, Antimicrob Agents Chemother (1980) 18:741-745, as reported in Chem Abstracts (1981) 94:26701v, reported that virus strains sensitive to acyclovir (9-(2-hydroxyethoxymethyl) guanine) induced production of DNA polymerases which were sensitive to its triphosphate. The same group, in a report by Bauer, D. J., et al, Dev Antiviral Therapy (1980) 43:51, as reported in Chem Abstracts (1981) 94:167716r disclose that acyclovir is effective in vitro against Varicella-Zoster, Epstein-Barr virus, cytomegalovirus, and "B" virus, and postulate that it provides its antiviral activity by being a substrate for phosphorylation by a viral thymidine kinase, such as that specified by the herpes virus, and, in the resulting triphosphate form, inhibits herpes virus DNA polymerase.
It has now been found that a series of phosphonates containing open chain ethers in lieu of ribose or deoxyribose residues in analogs of purine nucleosides are effective as cytotoxic agents, both against herpes-type DNA virus, for example, cytomegalovirus, and against RNA virus, for example, HIV. While these analogs appear similar to acyclovir in general chemical structure, they actually are not, since the phosphonate compounds are markedly different from the nonphosphorylated acyclovir. It is also clear that the mechanism of action for the compounds of the invention in preventing proliferation of viral infection cannot be the same as that for acyclovir, since phosphorylation by viral thymidine kinase cannot occur.
After the date of the disclosure herein, publications have appeared disclosing anti-herpes activity of 9-(3-phosphono-1-propoxymethyl) guanine (EPO Publication No. 0173,624, published May 3, 1986) and 9-(3-phosphono-1-hydroxymethyl-1-propoxymethyl) guanine (Duke, A. E., et al., Antiviral Res (1986) 6:299-308; Prisbe, E. J., et al., J Med Chem (1986) 29:671-675).